The glucocorticoid cascade hypothesis of aging predicts that hypersecretion of adrenal steroids such as cortisol or corticosterone (CORT) during adulthood will accelerate the aging process (Landfield et al., 1978; Sapolsky et al. 1986). A consistent finding in fetal alcohol exposed (FAE) animals is that they respond to moderate stress during adulthood with a hypersecretion of CORT. This long-term effect appears to appears to reflect an ethanol-induced disruption during gestation of the normal development of limbic structures such as hypothalamus and hippocampus that regulate stress, and consequently CORT secretion. Stemming from such disruption, FAE animals would be expected to be exposed to a greater than normal exposure to CORT during their lifetime. Based upon this combination of early disruption of limbic development and extended CORT exposure over the lifetime, we hypothesize that the regulation of behavioral and physiological processes that are integrated by the hypothalamus, such as circadian rhythms and stress-responsiveness, will decline more rapidly in aging FAE animals compared to controls. Preliminary data support this hypothesis by showing advanced onset in FAE animals for a) the age of anovulatory sterility, b) the age for loss of estrogen induction of proenkephalin mRNA in the hypothalamus, and c) the age at which impairment of thermoregulation in response to stress can be detected. Based upon these findings, the proposed studies are designed to test three hypotheses: 1) that prenatal ethanol exposure will accelerate the normal aging of physiological and behavioral systems integrated by the hypothalamus, 2) that exposing FAE animals to a subchronic stress regimen in early adulthood will exacerbate the increased rate of aging in these Systems, and 3) that handling during the postnatal stress hyporesponsive period will ameliorate the effects of prenatal ethanol exposure on the rate of aging. To address these hypotheses, we will study FAE animals across the lifespan. FAE males and females exposed to ethanol during the last week of gestation, the period of hypothalamic differentiation, will be compared to pair-fed and chow-fed controls at 4-5, 9-10, 18-19, and 24-25 months of age. Physiological and behavioral measures assessed will include circadian rhythms of locomotor activity, circadian rhythm o core body temperature, and circadian rhythms of hormone secretion. In addition, endocrine and core body temperature responses to restraint stress will be measured in order to unmask potential aging effects on HPA function at younger ages which may not be apparent under basal conditions. A potential relationship between prenatal exposure to subteratogenic levels of ethanol and an accelerated rate of aging has broad implications for NIH with regard to treatment, health education, and clinical services.